Homocystinuria is characterized by high serum homocysteine levels and leads to blood vessel damage, excretion of homocysteine in the urine, mental retardation, ectopia lentis, sparse blonde hair, convulsive tendency, thromboembolic episodes, and fatty changes of liver and is associated with defective formation of cystathionine synthetase.
Homocysteine is a homolog of cysteine and is produced by the demethylation of methionine, and is an intermediate in the biosynthesis of cysteine from methionine via cystathionine by cystathioninase.
High serum homocysteine-related blood vessel damage may account for up to 20% of U.S. heart attacks, 40% of strokes and 60% of peripheral venous occlusions, in addition to those in the placenta associated with neural tube defects in about 2,000 infants a year.
It has recently been disclosed that the B vitamins, folic acid and vitamin B12, by converting homocysteine to methionine, lower high serum homocysteine and thereby protect against high serum homocysteine-related blood vessel damage and nerve damage. The major sources of folic acid are foods that are often not ingested in sufficient amount, namely fresh fruits and vegetables, particularly the dark green leafy vegetables and orange juice. However, while vitamin B12 is in all animal protein, including meat, fish, poultry, eggs, milk and milk products, there is none in anything that grows out of the ground.
Folic acid and vitamin B12 are members of the vitamin B complex necessary for the normal production of red blood cells and nerve cells. Folic acid is present in peptide linkages in high quantities in liver, green vegetables and yeast. Vitamin B12 is present in high quantities in liver and other animal products.
Many plant and animal tissues contain folic acid as reduced methyl or formyl polyglutamates. Folates act as co-enzymes for processes in which there is transfer of a 1-carbon unit, as in purine and pyrimidine nucleotide biosynthesis, amino acid conversions such as histidine to glutamic acid and generation and use of formate. Absorption takes place in the small intestine. In the gut epithelial cells, polyglutamates are reduced to dihydro- and tetrahydra-folates, and absorbed bound to protein and transported in blood serum as methyl tetrahydrafolate. Some absorbed folate is excreted in the bile and re-absorbed, together with an amount not absorbed and excreted in the stool.
Vitamin B12 is necessary for taking a one-carbon unit from folic acid and delivering it to homocysteine to convert homocysteine to methionine. Vitamin B12 and folic acid are necessary for normal nerve function as well as for blood formation.
Vitamin Bis involved in a different pathway for getting rid of excess homocysteine, which pathway is usually less important than the B12-folate dependent pathway.
Vitamin supplements containing Folic Acid and/or vitamin B12 and or Vitamin B6 are known, however, such supplements contain other vitamins, phytochemicals and minerals such as iron and copper, or other antioxidant substances, including antioxidants, which destroy some of Vitamin B12 and also some of the folic acid.
In accordance with an aspect of the present invention there is provided a multiple vitamin supplement composition comprising folic acid and vitamin B12 that is essentially free of antioxidants.
In accordance with another aspect of the present invention there is provided a multiple vitamin supplement composition comprising folic acid, vitamin B12 and vitamin B6 that is essentially free of antioxidants.
In accordance with another aspect of the present invention there is provided a method of administering a multiple vitamin supplement composition for lowering high serum homocysteine levels to protect against the incidence of heart attack and other blood vessel related disorders.
In accordance with another aspect of the present invention there is provided a method of preparing a multiple vitamin supplement composition comprising folic acid and vitamin B12 that is essentially free of antioxidants.
In accordance with another aspect of the present invention there is provided a method of preparing a multiple vitamin supplement composition comprising folic acid, vitamin B12 and vitamin B6 that is essentially free of antioxidants.
In accordance with the primary aspect of the present invention there is provided a multiple vitamin supplement composition comprising folic acid and vitamin B12. The composition may also contain vitamin B6, wherein the composition is essentially free of antioxidants.
It has been shown that folic acid and vitamin B12 each have the ability to protect against high serum homocysteine-related blood vessel damage, as in some circumstances, does vitamin B6.
One problem with previous attempts at using vitamin supplements to prevent such cardiovascular problems from developing is that folic acid supplements taken alone are unsafe since they allow unrecognized genetically predisposed vitamin B12 deficiency to produce irreversible nerve damage in susceptible populations. Susceptible populations include the elderly (those at least about 50 years of age) and women of African American descent in their child-bearing years.
Accordingly, the multiple vitamin supplement composition of the present invention comprises folic acid and vitamin B12, and may also contain vitamin B6. The addition of vitamin B12 lowers to normal the vitamin B12-deficiency-produced high serum homocysteine found in millions of the elderly.
Vitamin B6, the other B vitamin involved in homocysteine metabolism is also added to the multiple vitamin supplement of the present invention. The addition of vitamin B12 and vitamin B6 further metabolizes homocysteine and lowers serum homocysteine levels.
In a preferred embodiment, the multiple vitamin supplement of the present invention contains 400 micrograms of folic acid, 100 micrograms of vitamin B12 and 10 milligrams of vitamin B6.
The present invention departs from the prior art in the discovery that the multiple vitamin supplement composition as described above must be essentially free of antioxidants. Antioxidants, including but not limited to other vitamins, minerals such as iron and copper, and other phytochemicals, destroy not only the vitamin B12 in the multiple vitamin supplement but also some of the folic acid in the supplement once the vitamin dissolves in the alimentary tract.
By xe2x80x9cessentially freexe2x80x9d it is meant that the vitamin composition of the present invention must not contain an amount of antioxidants which would tend to damage and inactivate some of the vitamin B12 and/or folic acid of the vitamin supplement when dissolved in the digestive tract. The presence of lower amounts of antioxidants would not render the vitamin composition of the present invention ineffective or of reduced effectiveness. Thus, supplemental vitamin C (a biochemically unbalanced synthetic product), which drives free radical formation from iron and heme (Herbert et al, J. Nutr., 126 (suppl. 4):1213S-1220S (1996)) destroys substantial vitamin B12 by converting it to useless, or even harmful, analogues. [Herbert, V., in Present Knowledge in Nutrition (7th Edition), Washington, D.C. ILSI Press (1996) pp. 191-205]. Free radical generation also destroys substantial folate and gastric intrinsic factor [Shaw et al, Alcohol, 7:153-157 (1990)] Further, effective Jan. 1, 1998, the FDA has mandated that all grains also be fortified with 140 xcexcg PGA (pteroylglutamic acid or folic acid) per 100 g grain. Such grains are currently fortified with iron due to an old mandate when negative iron balance was more widespread than the current 6% of all Americans. Also, it has only been learned recently that about 12% of Americans could be harmed by fortifying grains with iron because these persons are heterozygous for hemochromatosis. Many cereals and other products are also fortified with vitamin C.
More recently, based on Framingham data, Jacques et al (New England J. Medicine, 340:1449-1454 (1999)) have reported that, while fortification of grains with folic acid (PGA) in elderly adults increased serum folate and decreased serum homocysteine, the difference in mean homocysteine was largely due to differences in vitamin B12 and vitamin B6 status between users of B vitamin supplements and non-users. This supports earlier studies that by age 65, about 49% of otherwise healthy elderly adults no longer absorb vitamin B12 from food [see: Flynn et al, J. Am. Coll. Nutr., 16:258-267 (1997); Miller et al, FASEB J., 13:A936 (1997); Herbert, FASEB J., 13:A227 (1999)] as determined by low sodium holotranscobalamin II (holo TC II), a surrogate Schilling test, and that about 60% of this 49% had vasculotoxically high ( greater than 17) serum homocysteine, and that 100 xcexcg of crystalline vitamin B12 orally daily (with malabsorption, 500 xcexcg of vitamin B12 intranasally weekly) permanently sustains normal serum total and TCII vitamin B12 levels and keeps homocysteine normal. The reason why crystalline vitamin B12 and not vitamin B12 from food is superior is that, in the natural progression of genetically predisposed gastric atrophy, loss of gastric acid and enzymes precedes loss of intrinsic factor (IF) by years. Thus, without the acids and enzymes, vitamin B12 is not split from the proteins in food and is lost in the stool. However, crystalline vitamin B12 is free of peptide bonds and is normally absorbed via the physiologic IF-dependent mechanism. With no IF, about 1% of any oral dose of crystalline vitamin B12 is absorbed by mass action diffusion. Only 0.1 xcexcg vitamin B12 need be absorbed daily to sustain otherwise normal health. Thus, lower mean serum folate in the elderly is large vitamin B12 deficiency gut megaloblastosis producing malabsorption of folate, corrected by vitamin B12 therapy, and lower red cell folate is secondary both to availability of vitamin B12 to transport folate into red cells and to keep it in the red cells by polyglutamating it.
The components of the multiple vitamin supplement of the present invention are co-enzymes which act in accordance with methionine synthetase and cystathioninase and facilitate the production of methionine and cysteine from homocysteine. This lowers the serum level of homocysteine and the high level of heart attacks and other vascular damage and nerve damage associated therewith. The presence of antioxidants in the vitamin composition tends to inactivate the vitamin B12 and folic acid components of the vitamin composition once the vitamin composition is processed in the alimentary tract.
Therapeutic treatment with the multiple vitamin supplement of the present invention may involve administration to persons prophylactically, that is to prevent, retard or reduce the severity of future occurrence of the disease or its clinical manifestations.